The film opens with a satellite falling out of orbit and hurtling toward Earth.
In Brazil, Augustus Gibbons (Samuel L. Jackson) is trying to recruit Neymar, Jr. in a restaurant for a position as the next xXx agent. Neymar declines because he doesn't see himself as a hero. Moments later, a thief enters and tries to rob the place with a gun. Neymar grabs a napkin dispenser and kicks it at the guy's head. Gibbons is excited and starts trying to get Neymar in the program, but the satellite crashes down and blows the place up.
At the CIA headquarters, Jane Marke (Toni Collette) is telling her colleagues about what caused the satellite to crash: a military device known as Pandora's Box. The people that crashed the satellite can use Pandora's Box to bring any other military satellite down like a warhead. Meanwhile, four people - Xiang (Donnie Yen), Serena (Deepika Padukone), Talon (Tony Jaa), and Hawk (Michael Bisping) - infiltrate the headquarters and start taking out all the agents one by one. Xiang is quick with his hands and feet, and he swipes Pandora's Box from them. The team makes their escape. Marke then tells her superior that Gibbons knew someone who could handle these guys.
Xander Cage (Vin Diesel) has been living in the Dominican Republic. He skis from a tower and picks up a skateboard from some people in town before riding his board to fix an electrical issue that allows everyone to view the soccer game. Xander then goes home to his girlfriend Lola (Ariadna Gutierrez), and then leaves her some love-making.
Xander goes to Santo Domingo and notices something suspicious. An American man sits next to him on a bench and leaves a bag on the ground. Xander opens it and sees a bomb inside. Immediately, a SWAT team comes in and tells Xander to not move, then to get on his knees. Xander starts being a smartass to annoy the captain. Marke steps out and admits to everything being a ruse, which Xander knew about already. Marke starts trying to get Xander to rejoin the xXx program and mentions that Gibbons is dead.
Xander joins Marke in a church as they discuss the situation with Xiang and his team. Xander isn't eager to rejoin the program as he has been enjoying his self-imposed exile, but he mentions someone he knows in London that can help.
In London, Xander meets his friend Ainsley (Hermione Corfield), who helps him track down Xiang and his team to a location in the Philippines. He then spends time with Ainsley's girls for some "undercover work".
As Xiang and his team are hiding out, Serena approaches him about Pandora's Box. She knows that they are being hunted and she wants to destroy the device, but Xiang says they need it for what they want to do.
Marke brings on a Special Forces team led by Paul Donovan (Tony Gonzalez) to help Xander. He and Donovan do not get along, and Xander ejects Donovan and his team from the plane while they're attached to a cargo load with a parachute. Xander says he doesn't want these guys watching his back, so he picks a few people who he does trust.
We first meet Adele Wolff (Ruby Rose) as she appears to be hunting a lion. In reality, she is stalking out a trio of hunters set to harm the lion, but Adele shoots the three of them in the leg and leaves them to be chased by the lion. Xander calls her first. Next is Tennyson Torch (Rory McCann), a mad driver with a record 198 crashes to his name. Finally is Nicks (Kris Wu), a DJ that serves as a great distraction. The three are brought in to meet with Xander and Marke to go over the mission. They aren't interested at first, but eventually decide to join.
The team meets Becky Clearidge (Nina Dobrev), a hyper tech specialist that gives the team some fresh gear like bionic gloves.
The team arrives in the Philippines to a hideout run by a man named Lazarus (Nicky Jam). Xander gives him 22.5% of their ammunition in order to gain entrance to the place. It looks like a nightclub with people dancing and playing music. Xander approaches Serena as Nicks plays DJ to distract Talon from following Xander. After some "foreplay", Xander meets Xiang. The three of them sit down as Adele is up in a tree with her rifle waiting for a chance to make her move. Xiang takes out some grenades in a game of Hot Potato to see how quick Xander is. Xander learns that Xiang and his team are xXx agents with their own agenda. Moments later, a team of Russian soldiers storms the place. Xander and Xiang's teams spring into action. Adele shoots the goons and then follows the others as Xiang and his team get away.
Later on, Xander chases after Xiang on motorcycles that are equipped to surf on water. They ride through the waves as Xander tries to take Pandora's Box. He succeeds, but when he gets back to shore, Serena shoots and destroys it, then decides to join the xXx team.
Marke informs the team that Pandora's Box was used to destroy a Russian stadium. The one Xander took was just a prototype. The team realizes that someone in the CIA was in on the plot to help Xiang. They review footage of when Xiang broke into the headquarters, and Xander sees that Director Anderson (Al Sapienza) was the only person not to flinch when Xiang arrived.
The team tracks down Xiang and his team. Xander chases Xiang on the streets while Tennyson brings Adele, Nicks, and Serena to chase after Hawk, which leads to them crashing vans (which sets Tennyson's record to 200 crashes). Xander and Xiang fight one-on-one before Xander continues chasing Xiang to a warehouse. They end up helping each other avoid the gunmen before they reach Anderson. Adele is in a building across the street trying to get a shot on Anderson, but can't see with the thermal reading because the heat is cranked up. Anderson admits he crashed the satellite that killed Gibbons. Xander stands by the window and tells Adele to "read between the lines". He holds up his fingers and makes an opening for Adele to shoot Anderson in the head.
Marke and her men recover Pandora's Box and they apprehend Xiang. As they are leaving on the jet, Marke gets a phone call and says to Xander that the xXx program has been shuttered, so the agents must be eliminated. She reveals her true intentions and shoots Xander three times. She then sends for an extraction team to get Xander and Xiang's teammates, but they quickly discover the team are a bunch of hitmen sent to kill them. Both teams join forces to fight back. Adele and Serena shoot at the villains, and even Becky gets in on the shooting (albeit a bit clumsy). They are then joined by Darius Stone (Ice Cube), the last xXx agent recruited by Gibbons back in 2005. He comes in with a grenade launcher and blows up the villains.
On the plane, Xander recovers thanks to some armor. He and Xiang team up to fight Donovan and his goons. Donovan breaks out the bionic gloves and starts punching all the equipment on the plane as Xander dodges the punches. They fight in the bathroom, and Donovan punches the toilet, causing him to burst a hole in the plane that Xander pushes him out of. Marke uses Pandora's Box to send a satellite to the safe house to kill the teams. She shoots Xiang but he notices her foot is stuck on a strap. He pulls a parachute open and sends Marke falling out of the plane. Xiang falls out with his own chute. Serena calls Xander to inform him that the satellite is headed their way. Xander flies the plane in the direction of the satellite kamikaze-style. He runs and jumps out of the plane before it collides with the satellite. He lands safely using a cargo load. Once at the bottom, he stomps on Pandora's Box, destroying it for good. Xander and Serena kiss, and then Darius pulls up in Xander's old car. The two xXX men meet for the first time.
The now larger team attends Gibbons' funeral. Xander is up at the top when he is visited by none other than Gibbons himself. He faked his death once again and is keeping a low profile. Gibbons is also glad that Xander is back in action. He tells Xander all he has to do is "kick some ass, get the girl, and try to look dope". Gibbons leaves with Neymar while Xander continues to watch the service.